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A strategy for changing plasma pralidoxime kinetics and, perhaps, effect in organophosphorus insecticide poisoning*

Eddleston, Michael; Buckley, Nicholas A.

doi: 10.1097/CCM.0b013e31820a839b

Clinical Pharmacology Unit, University/BHF Centre for Cardiovascular Science, National Poisons Information Service–Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK (Eddleston)

Professorial Medicine Unit, POW Clinical School, University of New South Wales, Sydney, Australia (Buckley)

The authors have not disclosed any potential conflicts of interest.

Intentional pesticide self-poisoning kills over 250,000 people every year, the majority in rural Asia (1). Organophosphorus (OP) insecticides are likely to be responsible for more than two-thirds of these deaths. As a result, intensive care units across Asia are currently ventilating 3000 to 6000 OP-poisoned patients (1). Although less common in industrialized countries, OP pesticide poisoning does occur and frequently requires intensive care resources (2).

Management of severely poisoned patients is difficult. In one Sri Lankan series of patients requiring intubation and ventilation, 50% died in intensive care (3). Treatment involves resuscitation, supportive care, and administration of a muscarinic antagonist, eg, atropine and an acetylcholinesterase reactivating drug such as pralidoxime (4). Although the role of atropine is unquestioned, the effectiveness of pralidoxime in self-poisoned patients has long been the subject of debate.

Pralidoxime was developed in the 1950s and was rapidly introduced into clinical practice, particularly by Namba and colleagues. Case reports showed dramatic improvement in the condition of patients with moderately severe occupational poisoning resulting from the highly toxic World Health Organization class IA OP parathion (5). As a result, the use of pralidoxime became standard care (6). However, some Asian clinicians, seeing patients ingesting large amounts of these highly toxic pesticides in acts of self-harm, did not see obvious benefit and questioned its effectiveness (reviewed in Eddleston et al [7]). One argument offered for this lack of effect was that the dose of pralidoxime was too small (8). Higher doses were recommended with obvious effects on affordability for the resource-poor locations where most patients present.

Back in 1978, Josselson and Sidell (9) reported that the intravenous coadministration of thiamine increased plasma pralidoxime concentration by reducing its renal clearance. The authors suggested that thiamine and oxime might compete for a common renal secretory mechanism. This finding offered a method for increasing the plasma concentration of pralidoxime at a reasonable cost. However, this finding and its clinical relevance were never followed up.

Kayouka and colleagues have now begun to do this. In this issue of Critical Care Medicine, they report a study in which they tested the involvement of organic cation transporters (OCTs) in the renal secretion of pralidoxime using Oct1/2 and Oct3 knockout mice (10). The plasma pralidoxime area under the curve was increased 2.4-fold in Oct1/2 knockout mice compared with control mice after intramuscular injection but not increased in Oct3 knockout mice; the importance of Oct1 vs. Oct2 could not be determined.

They also used tetraethylammonium (TEA), an inhibitor of OCT transporters, to assess the functional consequences of inhibiting OCT1/2 in a rat model of poisoning with paraoxon, the active metabolite of parathion. Preadministration of 75 mg/kg (but not lower doses) of TEA 15 mins (but not earlier) before pralidoxime increased the area under the curve of pralidoxime, confirming an effect on clearance. There was a pronounced and sustained effect on respiratory parameters; however, this first occurred at a time when the effect on clearance was not apparent in the plasma concentrations. The favorable effect of TEA + pralidoxime had worn off after 100 mins, yet the difference in pralidoxime concentration between rats receiving TEA and placebo increased over this time. Furthermore, the lack of effect of pretreatment at 30 mins indicates that TEA is rapidly eliminated (as shown by others [11]).

The best single explanation for these observations is that TEA increases distribution at the same time as it transiently and competitively inhibits clearance of pralidoxime. The OCTs are known to be involved in xenobiotic transport at the blood–brain barrier. Central nervous system concentrations of pralidoxime are only 5–10% of plasma concentrations (12); decreased transport of pralidoxime out of the brain may have improved its effect on central respiratory drive in this model.

These results are interesting but the relevance of this mechanistic model (with unformulated pesticide metabolite given subcutaneously, single intramuscular doses of antidotes, and lack of atropine or supportive care) to management of human poisoning is minimal. It should not be extrapolated and indeed it may be harmful to do so. OCTs are involved in clearance, biotransformation, and/or central nervous system distribution of many xenobiotics, including (for example) some anticholinesterases (13) Furthermore, OCT2 is involved in acetylcholine and other neurotransmitter transport (14). The potential for harmful interactions from OCT inhibitors is considerable.

In addition, as discussed by the authors, recent clinical trial evidence questions the potential for any clinical benefit from pralidoxime. One Indian trial compared a high dose of pralidoxime iodide (1 g/hr for 48 hrs, then 1 g every 4 hrs) with a lower dose (1 g every 4 hrs) until patients were weaned off ventilators (15). They found a benefit of the higher dose with reduced need for intubation, ventilation, and atropine requirements. However, this trial did not recruit severely ill patients, intubated the majority of patients at baseline, and treated all patients in an intensive care unit. Such care is not possible for the great majority of poisoned patients in Asia but may be relevant to an intensive care unit in industrialized countries.

A second clinical trial in Sri Lanka recruited all OP-poisoned patients requiring atropine admitted to two resource-poor district general hospitals, including severely ill patients (16). Few patients were treated in an intensive care unit with only 17% being intubated at baseline despite being, as a group, more severely poisoned. A high dose of pralidoxime chloride (2-g loading dose over 20 mins, then 0.5 g/hr until atropine was no longer required or 7 days) was compared with placebo. In contrast to the first study, this trial found no evidence of benefit from a high dose of pralidoxime. This study was methodologically better than the first and (in contrast to the views of Kayouka et al [10]) actually had much higher power for the most important outcome (survival), because power is determined by the number of events (deaths) in each study: nine (15) vs. 48 (16).

These studies indicate that increasing the concentration of pralidoxime with an OCT1/2 blocker may not benefit patients. The authors comment on the high toxicity of TEA necessitating the use of other OCT blockers in humans and yet, ironically, TEA has a very similar rat LD50, and low safety margin, as pralidoxime itself.

On a more positive note, this work should lead on to further studies to see if a clinically safe and affordable blocker (the authors report unpublished data that thiamine is not effective in their rat model) can lead to a less expensive, and perhaps more effective and safer, dosing regimen of pralidoxime. Research by these authors highlights the potential for adverse (as well as favorable) drug interactions. Drugs may inhibit OCT (eg, cimetidine), and severe OP poisoning can be produce renal failure (17). Both would be expected to lead to accumulation of pralidoxime (18). We should not assume that such interactions will be beneficial in our patients. Indeed, if anything, this new evidence on yet more sources of variability in pralidoxime kinetics should perhaps make people question whether lower or shorter duration dosing regimens of pralidoxime may be safer.

Michael Eddleston

Clinical Pharmacology Unit

University/BHF Centre for Cardiovascular Science

National Poisons Information Service–Edinburgh

Royal Infirmary of Edinburgh

Edinburgh, UK

Nicholas A. Buckley

Professorial Medicine Unit

POW Clinical School

University of New South Wales

Sydney, Australia

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*See also p. 803.


pesticide poisoning; suicide; antidote; pralidoxime; renal transporters; pharmacokinetics

© 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins